Influence of SIGLEC9 polymorphisms on COPD phenotypes including exacerbation frequency.

BACKGROUND AND OBJECTIVE: The exacerbation-prone phenotype of COPD is particularly important, as exacerbations lead to poor quality of life and disease progression. We previously found that COPD patients who lack Siglec-14, a myeloid cell protein that recognizes bacteria and triggers inflammatory responses, are less prone to exacerbation. We hypothesized that the variations in other SIGLEC genes could also influence COPD exacerbation frequency, and investigated the association between SIGLEC9 polymorphisms and the exacerbation-prone phenotype of COPD. METHODS: We examined whether SIGLEC9 polymorphisms affect the frequency of COPD exacerbation in 135 subjects within our study population, and also analysed the correlation between the genotypes and the severity of airflow obstruction and emphysema in 362 Japanese smokers including 244 COPD patients. The association between these single nucleotide polymorphisms (SNPs) and COPD phenotypes were also assessed in a Caucasian population of ECLIPSE study. The effects of these coding SNPs (cSNPs) on Siglec-9 protein functions were analysed using in vitro assays. RESULTS: The G allele of rs2075803 and rs2075803 G/rs2258983 A(GA) haplotype in SIGLEC9 was associated with higher frequency of exacerbations and the extent of emphysema in COPD. These results did not replicate in the ECLIPSE study. A myeloid cell line expressing the Siglec-9 variant corresponding to GA haplotype produced more TNF-α than the one expressing the variant corresponding to the other major haplotype. CONCLUSION: The SIGLEC9 rs2075803 G/rs2258983 A haplotype, which corresponds to a Siglec-9 variant that is less effective at suppressing inflammatory response, may be a risk factor for the development of emphysema.

Atrial and Ventricular Arrhythmia-Associated Factors in Stable Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Supraventricular and ventricular premature complexes (SVPC and VPC, respectively) are associated with chronic obstructive pulmonary disease (COPD) and with increased mortality in COPD patients. However, there are few reports on the causes of arrhythmia in COPD patients. OBJECTIVES: This study explores the associations between cardiopulmonary dysfunction and COPD by comparing patients with defined arrhythmias (>100 beats per 24 h) and those without, based on 24-hour electrocardiogram (ECG) recordings. METHODS: Patients with arrhythmia underwent a 24-hour ECG and subsequent pulmonary function tests, computed tomography, ECG, 6-min walk test (6MWT), and BODE (body mass index, airflow obstruction, modified Medical Research Council Dyspnoea Scale, exercise capacity) index calculation. RESULTS: Of 103 study patients (71 COPD patients and 32 at-risk patients), 36 had VPC, 45 had SVPC, 20 had both, and 42 had neither. The predicted post-bronchodilator forced expiratory volume in 1 s, the proportion of low-attenuation area on computed tomography, and BODE index values were significantly worse in the SVPC and VPC groups compared with the corresponding reference groups. Patients in the VPC group showed significantly increased right ventricular pressure and increased desaturation in the 6MWT compared with the reference group. In the multivariate analyses, bronchodilator use was a significant risk factor in the SVPC group, whereas in the VPC group, all parameters of the BODE index except for the dyspnoea score were identified as risk factors. CONCLUSIONS: Increased SVPC might be caused by bronchodilator use, whereas increased VPC is likely related to the peculiar pathophysiology of COPD.

Diagnostic Values For Club Cell Secretory Protein (CC16) in Serum of Patients of Combined Pulmonary Fibrosis and Emphysema.

Combined pulmonary fibrosis and emphysema (CPFE) is an under-recognized syndrome for which the diagnostic use of serum biomarkers is an attractive possibility. We hypothesized that CC16 and/or TGF-ß1 or combinations with other biomarkers are useful for diagnosing CPFE. Patients with respiratory symptoms and a smoking history, with or without chronic obstructive pulmonary disease, were divided into the following three groups according to findings of high-resolution computed tomography of the chest: controls without either emphysema or fibrosis, patients with emphysema alone, and patients compatible with the diagnosis of CPFE. Serum concentrations of CC16, TGF-ß1, SP-D, and KL-6 were measured in patients whose condition was stable for at least 3 months. To investigate changes in biomarkers of lung fibrosis in patients with a life-long smoking history, additional measurements were performed on the patients with idiopathic pulmonary fibrosis (IPF) of smoking history. The mean age of the first three groups was 68.0 years, whereas that of the IPF group was 71.8 years, and the groups contained 36, 115, 27, and 10 individuals, respectively. The serum concentration of CC16 in the four groups was 5.67 ± 0.42, 5.66 ± 0.35, 9.38 ± 1.04 and 22.15 ± 4.64 ng/ml, respectively, indicating that those patients with lung fibrosis had a significantly higher concentration. The combined use of CC16, SP-D, and KL-6 provided supportive diagnosis in conjunction with radiological imaging in diagnosis of CPFE. We conclude that a combination of biomarkers including CC16 could provide useful information to screen and predict the possible diagnosis of CPFE.

Association of group component genetic variations in COPD and COPD exacerbation in a Japanese population.

BACKGROUND AND OBJECTIVE: Vitamin D supplementation can decrease the vulnerability to pulmonary infections. Therefore, it is speculated that the genes related to vitamin D metabolism are associated with an exacerbation-prone phenotype in chronic obstructive pulmonary disease (COPD). Because genetic variations of group component (GC) affect immunological capacity and serum vitamin D concentration, they could also affect the susceptibility to COPD exacerbation and the disease progression. We investigated the association between GC genetic variations and COPD and its exacerbation frequency in a Japanese population. METHODS: We performed genotype analysis of 361 COPD patients and 219 controls to identify two coding single nucleotide polymorphisms of GC, rs4588 and rs7041. We examined whether these polymorphisms were associated with the frequency of COPD exacerbation and analysed the correlation between the genotypes, COPD, emphysema severity and COPD progression, namely, the annual decline in airflow obstruction and diffusing capacity. RESULTS: Subjects with a C allele at rs4588 exhibited a higher frequency of exacerbations (P = 0.0048), greater susceptibility to chronic obstructive pulmonary disease (P = 0.0003), and emphysema (P = 0.0029), and a tendency for rapid decline of airflow obstruction (P = 0.0927). CONCLUSIONS: GC variations may affect exacerbation susceptibility, possibly leading to COPD worsening and its progression.

Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the "infection-inflammation-exacerbation" axis of COPD disease progression, and may represent promising targets for therapeutic intervention.

Long-term oxygen therapy in Japan: history, present status, and current problems.

Historically, the progress of long term-oxygen therapy (LTOT) in Japan has been characterized by collaboration among academic groups, policy makers, and industrial companies. The public health insurance program has covered the cost of LTOT since 1985. Thomas Petty's group in Denver enthusiastically carried out the public implementation of LTOT and conveyed the concept of pulmonary rehabilitation for the processing with LTOT. Although the target diseases of LTOT in Japan tended to be chronic obstructive pulmonary disease or sequelae of primary lung tuberculosis, it was soon applied for cardiac diseases as well as other pulmonary diseases. Together with increasing medical costs for geriatric patients, the political conversion from hospital based care of a traditional style to home care system has been performed, with two background reasons: the improvement of quality of life of patients and the reduction of the medical expense. Presently, LTOT plays a pivotal role in the successful implementation of home respiratory care for elderly patients. In addition, this promotes comprehensive pulmonary rehabilitation, a team approach, and close liaisons between primary care and hospitals. Currently, the total number of patients using LTOT exceeds 150,000. In Japan, LTOT resulted in an advancement in the medical care as well as in administrative decision to introduce it as a nationwide system after analyzing the results of opinion polls of patients with respiratory failure. However, the recent great earthquake in East Japan revealed that many unresolved problems remain for these patients, and these issues are of great concern.

α1,6-Fucosyltransferase (Fut8) is implicated in vulnerability to elastase-induced emphysema in mice and a possible non-invasive predictive marker for disease progression and exacerbations in chronic obstructive pulmonary disease (COPD).

Fut8 (α1,6-Fucosyltransferase) heterozygous knock-out (Fut8(+/-)) mice had an increased influx of inflammatory cells into the lungs, and this was associated with an up-regulation of matrix metalloproteinases, MMP-2 and MMP-9, after treatment with porcine pancreatic elastase (PPE), exhibiting an emphysema-prone phenotype as compared with wild type mice (Fut8(+/+)). The present data as well as our previous data on cigarette-smoke-induced emphysema [8] led us to hypothesize that reduced Fut8 levels leads to COPD with increased inflammatory response in humans and is associated with disease progression. To test this hypothesis, symptomatic current or ex-smokers with stable COPD or at risk outpatients were recruited. We investigated the association between serum Fut8 activity and disease severity, including the extent of emphysema (percentage of low-attenuation area; LAA%), airflow limitation, and the annual rate of decline in forced expiratory volume in 1 s (FEV(1)). Association with the exacerbation of COPD was also evaluated over a 3-year period. Serum Fut8 and MMP-9 activity were measured. Fut8 activity significantly increased with age among the at risk patients. In the case of COPD patients, however, the association was not clearly observed. A faster annual decline of FEV(1) was significantly associated with lower Fut8 activity. Patients with lower Fut8 activity experienced exacerbations more frequently. These data suggest that reduced Fut8 activity is associated with the progression of COPD and serum Fut8 activity is a non-invasive predictive biomarker candidate for progression and exacerbation of COPD.

Multicentre comparison of self-management in patients with COPD.

In patients with COPD, self-management plays an important role in disease management. Recently, self-management programmes have expanded patient education practices to include a variety of disease management techniques. We hypothesised that COPD patients have insufficient and/or different self-management needs according to institution. We compared information needs of patients between specialised clinics in Canada (SCC) and Japan and a hospital outpatient clinic in Japan (HCJ), all employing different self-management interventions. This cross-sectional study evaluated patients' information needs for disease management using the Lung Information Needs Questionnaire (LINQ). Furthermore, we assessed pulmonary function tests, modified Medical Research Council (mMRC) dyspnoea scale and frequencies of hospitalisations and emergency visits. The total number of patients was 183. Those attending SCC were younger (p=0.047), with lower forced expiratory volume in 1 s % predicted (p<0.0001), and scored higher on the mMRC dyspnoea scale. Total LINQ scores showed differences between institutions (p<0.0001). There was no difference for the smoking domain; however, SCC recorded significantly lower information needs for all other domains (p<0.02). No significant difference in emergency visits was seen between institutions, but HCJ recorded the highest rate of emergency visits, while SCC had significantly higher rates of hospitalisation (p=0.004). Differences were seen for frequency and duration of education between institutions. These results highlight the differences in information needs by institution and the importance of assessing individual needs. We believe, despite representing only one aspect of self-management, our findings reflect real-world circumstances, adding to the argument that self-management education should be structured, but flexible, to meet the changing needs of COPD patients.

A Non-Interventional, Cross-Sectional Study to Evaluate Factors Relating to Daily Step Counts and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease: STEP COPD.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults. As lower PA is associated with increased mortality, improving PA is an important objective for COPD management. This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA. Patients and Methods: Outpatients aged ≥40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled. Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics. Secondary outcomes included further investigation of the influence of patient characteristics on PA. Results: Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated. Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3). Median (Q1, Q3) durations of PA at ≥3 (moderate-to-vigorous) and ≥2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively. For >30% of patients, time spent in ≥3 METs activity was ≤10 minutes. Unemployment was significantly correlated with reduced activity time (≥3 and ≥2 METs) and step count. Severe GOLD stage was significantly correlated with reduced activity time (≥3 and ≥2 METs). High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥3 METs) and step count. Patients tended to overestimate the time spent in activities requiring ≥2 METs in their subjective reports compared with activity monitor measurements. Conclusion: Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II. Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA. Clinical Trial Registration: NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp).

Gender Differences in Chronic Obstructive Pulmonary Disease Using the Lung Information Needs Questionnaire.

Aim: To investigate gender-related information needs in patients with chronic obstructive pulmonary disease (COPD) using the Lung Information Needs Questionnaire (LINQ). Design: Cross-sectional, prospective cohort study. Methods: Patients with COPD receiving standardized self-management education including information regarding disease knowledge, medications, avoidance of exacerbation, smoking cessation, exercise, and nutrition were included. Gender differences were assessed by pulmonary function tests, 6-minute walking test, modified Medical Research Council dyspnea scale, Mini-Mental State Examination, St. George's Respiratory Questionnaire, and LINQ. Results: A total of 122 patients were enrolled. Females displayed significantly higher information needs for total LINQ score (p < .001), avoidance of exacerbation (p < .03), and nutrition (p < .006). Significant correlations were seen between total LINQ score and gender (p = .001), forced expiratory volume in 1 second, % predicted (p = .003), and Mini-Mental State Examination (p = .002) for male patients. In females, modified Medical Research Council dyspnea scale was correlated with the total LINQ score (p = .04).

Effect of tiotropium/olodaterol on sedentary and active time in patients with COPD: post hoc analysis of the VESUTO® study.

Background: Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD. Patients and methods: Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0-1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69). Results: Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0-1.5 MET activity by 8.64 mins (p=0.040) and significantly increased the duration of ≥2.0 MET and ≥3.0 MET activity by 6.51 mins (p=0.017) and 2.60 mins (p=0.008), respectively, compared with tiotropium alone. Subgroup analyses showed that better lung function, milder dyspnea, and higher levels of physical activity at baseline were associated with reduced sedentary time and increased duration of physical activity. Conclusion: Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).

Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity.

Purpose: This study evaluated the efficacy of tiotropium/olodaterol vs tiotropium on lung function, exercise capacity, and physical activity in patients with COPD. Patients and methods: A total of 184 patients aged ≥40 years with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) received tiotropium/olodaterol for 6 weeks, then tiotropium for 6 weeks, or vice versa. The primary endpoint was inspiratory capacity (IC) at peak post-dose. Results: Adjusted mean IC after 6-week treatment was 1.990 L with tiotropium/olodaterol vs 1.875 L with tiotropium (difference: 115 mL; 95% CI: 77, 153; p<0.0001). Forced expiratory volume in 1 s (difference: 105 mL; 95% CI: 88, 123), forced vital capacity (difference: 163 mL; 95% CI: 130, 197), and slow vital capacity (difference: 134 mL; 95% CI: 91, 176) improved with tiotropium/olodaterol (all p<0.0001). Adjusted mean 6-min walk distance was similar between treatments in the overall population but was significantly increased with tiotropium/olodaterol in the subgroup with Global Initiative for Chronic Obstructive Lung Disease stage III/IV at baseline (difference: 18.1 m; 95% CI: 2.3, 33.9; p=0.0254). In a post hoc analysis, tiotropium/olodaterol improved the values for ≥2.0 metabolic equivalents (difference: 5.0 min; 95% CI: 0.4, 9.7; p=0.0337). Conclusion: Tiotropium/olodaterol significantly improved IC compared with tiotropium and potentially enhanced the exercise capacity in COPD patients. A slight improvement in physical activity of relatively more than moderate intensity was also seen with tiotropium/olodaterol.

Effectiveness of home-based exercise in older patients with advanced chronic obstructive pulmonary disease: A 3-year cohort study.

AIM: To determine whether home-based exercise can improve clinical outcomes in older patients with advanced chronic obstructive pulmonary disease using long-term oxygen therapy. METHODS: Information was provided to improve chronic obstructive pulmonary disease self-management before the onset of the present prospective 3-year cohort study. Patients selected either home-based exercise using a lower-limb cycle machine (ergo-bicycle; group E), or usual exercise (group U). To assess self-management, the Lung Information Needs Questionnaire was evaluated every 6 months. Clinical outcomes included the 6-min walk test, pulmonary function tests, the body mass index, airflow obstruction, dyspnea and exercise index, St. George's respiratory questionnaire, and the number of exacerbations and hospitalizations. RESULTS: A total of 136 patients (group E = 72; group U = 64), with a mean age of 74.2 years were enrolled. Total Lung Information Needs Questionnaire scores improved over 3 years for group E (P = 0.003). The distance of the 6-min walk test was well maintained in group E, but significantly decreased in group U (P < 0.001). The percentage of forced expiratory volume in 1 s at baseline was lower in group E (P = 0.016), but was maintained over 3 years, whereas a significant reduction was seen in group U (P = 0.001). The body mass index, airflow obstruction, dyspnea and exercise index significantly worsened in both groups over 3 years (group E: P = 0.011; group U: P < 0.001), whereas a significant decrease in the number of exacerbations was noted in group E (P = 0.009). CONCLUSIONS: Patients who undertook home-based exercise using an ergo-bicycle were able to maintain clinical outcomes including 6-min walk test distance and percentage of forced expiratory volume in 1 s predicted, and recorded fewer exacerbations over 3 years. Geriatr Gerontol Int 2018; 18: 42-49.

Environmental influence on the measurement of exhaled nitric oxide concentration in school children: special reference to methodology.

INTRODUCTION: Measuring exhaled nitric oxide (eNO) is a noninvasive and useful method for evaluating the correlation between airway inflammation and air pollution. The method is being used in studies; however, the effects of polluted air on eNO values are poorly understood. If polluted air significantly affects eNO concentrations, then it would be hard to evaluate the concentration of eNO, particularly in epidemiological measurements to detect the effects of airway inflammation, such as that in bronchial asthma. Thus, we hypothesized that short-term exposure to air pollution affects eNO values. PURPOSE: To study the effects of environmental nitrogen oxides on the measurement of eNO concentration. SUBJECTS AND METHODS: A total of 19 school children who lived on a large street with heavy traffic with random allocation were studied. Subjects with bronchial asthma were identified with a questionnaire. Suspended particulate matter. including particulate matter with an aerodynamic diameter < or =2.5 microm (PM(2.5)), optical black carbon, nitric oxide (NO), nitric dioxide (NO(2)), and nitrogen oxides (NO(X)), were measured at a fixed place along the street every hour for 11 consecutive days. The concentrations of NO and NO(2) for each subject were measured by an individual 2-pyenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl sampler, and the concentration of eNO was measured with the off-line method. RESULTS: Of 19 subjects, 3 were found to have bronchial asthma. The level of each pollutant for 11 days peaked during the mornings (6;9 a.m.) and evenings (6;9 p.m.) due to traffic jams; average eNO values in healthy subjects and those with asthma were 27.1 +/- 9.7 and 57.7 +/- 18.6 ppb (p=0.098), respectively. It was found that the eNO value remained high when the mean values of various pollutants remained high for 8 hours before the measurements. It was estimated that the mean eNO values increased by 1.08 ppb (95% CI: 0.72;1.45) when the mean NO(X) value for the previous 8 hours reached approximately 10 ppb. CONCLUSION: We conclude that short-term exposure to polluted air of at least 8 hours before measurement affects eNO values. Therefore, caution should be exercised when measuring eNO value in epidemiological studies.

Study Design of VESUTO®: Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD. METHODS: A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD. RESULTS: A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints. CONCLUSION: The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) combination therapy on patients' physical activities as well as lung function. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015). FUNDING: The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

[Cost analysis for inpatient therapy for patients with acute exacerbations of chronic obstructive pulmonary disease].

Acute exacerbation of COPD (AE-COPD) is a major problem influencing patient outcome, increasing both economic burden and mortality. We investigated: 1) the direct medical cost for inpatients with AE-COPD, and 2) factors that contribute to the higher cost of AE-COPD. A total of 131 episodes in 99 patients (mean age: 77.9 yr) with AE-COPD (79 men and 20 women) were investigated. Mean FEV1 and FEV1% pred were 0.97L and 42.7%, respectively. Mean length of stay (LOS) was 23.9 days and longer LOS was correlated with poorer basic activities of daily living (ADL). Mortality during admission and one month after discharge was 4.8%, however, it reached 20.2% one year later. The mean total cost for each admission was 690,000 yen (median 613,000 yen). Univariate analysis indicated that advanced age, hypoxemia, hypercapnea, systemic steroid use and reduction of ADL significantly correlated with increased total cost over the median cost. Multivariate analysis showed that factors significantly correlated with high medical cost over the median cost were observed in patients with a reduction of ADL (p < 0.001), hypoxemia OR 4.13 (95% CI: 1.54-11.05), systemic steroid use OR 3.14 (95% CI: 1.07-9.26), and reduced ADL OR 2.76 (95% CI: 1.04-7.30). However, neither advanced age nor severity of COPD, body mass index, or comorbidity significantly correlated with the total cost. We concluded that reduction of ADL in elderly COPD patients closely correlated with increased cost due to acute exacerbation. Therefore, pulmonary rehabilitation should be implemented from the perspective of reducing economic health burden.

[A case of multicentric Castleman disease showing diffuse cystic change in the lung].

A 31-year-old woman was admitted to our hospital because of progressive dyspnea and chest X-ray abnormality. She was given a diagnosis of bronchial asthma 3 years previously. She had received medical treatment, but her dyspnea did not improve. Chest CT showed multiple thin-walled cysts and centrilobular nodules throughout both lungs. Video-assisted thoracoscopic lung biopsy revealed remarkable plasmacytic infiltration in the bronchioles and its surrounding interstitium. Small cystic lesions were detected and with remarkable mural plasmacytic infiltration. The immunohistochemistry showed infiltrated plasmacytes with polyconal characteristics. Her biochemical examinations showed polyclonal hyperimmunoglobulinemia and a high range of serum IL-6. In addition, CT scans showed multiple mediastinal and intraperitoneal lymphadenopathy. From these examinations, she was given a diagnosis of multicentric Castleman disease (MCD) with pulmonary involvement showing diffuse cystic change. This case showed an unusual pattern of MCD with pulmonary involvement. However, we suggest that MCD also should be considered as a differential diagnosis in cases with diffuse lung cystic changes.

The Neutrophil to Lymphocyte Ratio Is Related to Disease Severity and Exacerbation in Patients with Chronic Obstructive Pulmonary Disease.

Objective Although chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, the association between the neutrophil to lymphocyte ratio (NLR; an indicator of inflammation) and the clinical status of COPD has not been well studied. We hypothesized that the NLR is associated with disease severity and exacerbation in COPD patients. Methods We performed blood testing, pulmonary function testing, chest computed tomography, a body composition analysis, and a 6-minute walk test and applied the modified Medical Research Council (MMRC) dyspnea scale for 141 stable COPD patients. In addition, we calculated the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index to evaluate the disease severity. Finally, we examined the association between the NLR and clinical parameters in stable COPD patients, and we further investigated changes in the NLR between exacerbation and the stable state. Results The NLR was positively correlated with the BODE index, extent of emphysema, and MMRC score (p<0.001 for all), while inversely correlated with airflow obstruction (p<0.001), body mass index (p<0.001), fat-free mass index (p=0.001), and the 6-minute walk distance (p<0.001). We obtained the NLR during exacerbation from 49 patients. The NLR was significantly higher at exacerbation compared to the stable state (p<0.001). Conclusion The NLR was associated with disease severity and exacerbation in COPD patients. Therefore, the usefulness of the NLR in COPD patients should be elucidated in clinical settings in future investigations.

Relationship between serum cardiac troponin T level and cardiopulmonary function in stable chronic obstructive pulmonary disease.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) in serum is a useful marker of acute myocardial injury, yet information is limited in patients with chronic obstructive pulmonary disease. We aimed to explore the association between hs-cTnT levels and cardiac and pulmonary dysfunction in patients with stable chronic obstructive pulmonary disease and at-risk individuals. METHODS: We examined community-dwelling adults with/without chronic obstructive pulmonary disease, with a life-long smoking history, current symptoms of dyspnea during exertion, prolonged coughing, and/or sputum. Serum hs-cTnT concentrations were measured, and subjects underwent pulmonary function tests, high-resolution computed tomography of the chest, an echocardiogram, and a 6-minute walking test. RESULTS: Eighty-six stable patients were identified (mean age 65.5 years; predicted forced expiratory volume in 1 second [FEV1% predicted] 75.0%). Their overall mean hs-cTnT level was 0.008 ng/mL. Logarithmically transformed hs-cTnT levels significantly and positively correlated with age, smoking index, serum high-sensitivity C-reactive protein levels, right ventricle systolic pressure, low attenuation area percentage, and brain natriuretic peptide levels (range r=0.231-0.534, P=0.000 to P=0.042). Further, logarithmically transformed hs-cTnT values significantly and negatively correlated with forced vital capacity, FEV1% predicted, diffusion capacity, arterial oxygen tension, and 6-minute walking distance (range r= -0.482 to -0.377, P=0.000 to P=0.002). Multivariate analyses showed that hs-cTnT values varied independently according to the following three parameters: high-sensitivity C-reactive protein levels (B=0.157, ß=0.450, t=3.571, P=0.001), age (B=0.008, ß=0.352, t=2.789, P=0.009), and right ventricular systolic pressure (B=0.008, ß=0.280, t=2.202, P=0.035). CONCLUSION: Even in patients with stable chronic obstructive pulmonary disease, the serum troponin T concentration was controlled by at least three major factors, ie, systemic inflammation, advancing age, and right cardiac overload.

Long-term effects of gastrectomy in patients with spirometry-defined COPD and patients at risk of COPD: a case-control study.

OBJECTIVE: Comorbidities are characteristic of COPD. However, little is known about the secondary manifestations of COPD in the gastrointestinal tract. Therefore, we aimed to explore the long-term effects of gastrectomy in patients with spirometry-defined COPD or those at risk of COPD. PARTICIPANTS: Subjects included 87 patients either with COPD or at risk of COPD (symptomatic) who underwent gastrectomy between December 2003 and October 2013 (group A), and 174 patients either with COPD or at risk of COPD, matched by age (±5 years), sex, and forced expiratory volume in 1 second (FEV1) as percentage of predicted (FEV1% predicted) (±5%) (group B). METHODS: All patients underwent routine blood chemistry and pulmonary function tests, arterial blood gas analysis, 6-minute walk test (6MWT), high-resolution chest computed tomography scans, and nutritional assessments. RESULTS: The mean duration postgastrectomy was 18.3±15.4 years. The mean FEV1 and FEV1% predicted were 2.07±0.76 L and 74.6±24.5%, respectively. Univariate analysis indicated that group A patients had significantly lower body mass index, fat-free mass index, and serum hemoglobin and albumin concentration (all P=0.00), and walked a significantly shorter distance in the 6MWT (P<0.05). Multivariate linear regression analysis for the distance in the 6MWT indicated that increased residual volume (RV) to total lung capacity (TLC) as percentage of predicted (%RV/TLC) alone was an independent and significant predictor of reduced distances in the 6MWT. CONCLUSION: We concluded that nutritional insufficiency in patients with COPD (or those at risk of COPD) who previously underwent gastrectomy might lead to hyperinflation and consequently, decreased exercise capacity.